1. Field of the Invention
The present invention relates to a process for the preparation of [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonic acid and of the hemipentahydrate monosodium salt thereof useful in the treatment of osteoporosis.
2. Description of the Related Art
[1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonic acid (1), also shown in FIG. 1,
is otherwise known under the international non-proprietary name (INN) as risedronic acid.
The hemipentahydrate monosodium salt of [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonic acid is otherwise known under the international non-proprietary name (INN) as risedronate sodium.
Risedronate sodium is one of many bisphosphonates, which form a large group of medicines useful in the treatment of disorders caused by abnormal calcium metabolism, i.e., osteoporosis or Paget disease. Specifically, risedronate sodium is used in the treatment of postmenopausal osteoporosis, and is particularly used to reduce the risk of vertebral body fracture and femoral neck fracture.
The process for the preparation of [1-hydroxy-2-(3-pyridinyl)ethylidene]bisphosphonic acid is based mainly on the reaction of 3-pyridyl acetic acid with phosphorous acid and phosphorus chloride. Chemical literature references and patent descriptions specify that chlorobenzene, fluorobenzene and methanesulphonic acid are used as solvents in these routes of synthesis; the yield referred to in the literature is not greater than 52%.
Specifically, the European patent EP 0 186 405 B1 claims a reaction of 3-pyridyl acetic acid with phosphorous acid in chlorobenzene, where phosphorus trichloride is added.
Moreover, the Polish patent application P.346517 discloses a method for the preparation of risedronic acid by reacting 3-pyridyl acetic acid hydrochloride with phosphorous acid and phosphorus trichloride in chlorobenzene or fluorobenzene. The solvent is then removed, risedronic acid isolated, and reacted with an alkali metal or ammonium hydroxide, bicarbonate or carbonate, to yield an alkali metal salt or the ammonium salt of risedronic acid. The procedure, carried out in accordance with the description of Polish patent application P.346517, allows for obtaining risedronic acid with a yield of 49-50%.
Both 3-pyridyl acetic acid and phosphorous acid are not soluble in chlorobenzene and fluorobenzene. The entire process takes place in a heterogeneous system, which makes intermixing of reactants difficult. Isolating of the product is done by decantation of chlorobenzene or fluorobenzene from an amorphous oily reaction product. The yield in these experiments is not repeatable and ranges between 10 and 47%. The use of methanesulphonic acid as the solvent gives a product with a low yield (see, J. Org. Chem. 1995, 60; 8310-8312). An additional problem when carrying out the procedures is that methanesulphonic acid is highly reactive and toxic.